This proposal seeks funding to support the infrastructure of the Women's Health Study (WHS) for an additional 5 years, to accrue and validate a substantially increased number of cardiovascular disease (CVD) and cancer endpoints. With extensive information already available on randomized treatments, epidemiological risk factors, and genetic and biochemical data, this funding will allow the evaluation of clinically important questions related to CVD and cancer at a low cost of about $38 per participant per year. The WHS is a randomized trial of low-dose aspirin and vitamin E in the primary prevention of CVD and cancer among 39,876 female health professionals aged 45 years or older. Yearly questionnaires ascertain relevant health outcomes and demographic, lifestyle, and medical risk factor information. Morbidity and mortality follow-up rates are 96% and 100%, respectively. As part of NIH funding for the trial, pre-randomization blood samples from 28,345 participants were frozen and stored. With support from non-federal sources, DNA from all samples has been extracted and is now undergoing extensive genotyping for markers of hemostasis, thrombosis, and inflammation. All plasma samples have been assayed for a full lipid panel, high sensitivity C-reactive protein, and creatinine, and are now undergoing extensive phenotyping for additional inflammatory and hematologic markers. Trial funding will end in August 2004, with a mean treatment duration of 10 years and an expected total of 1004 CVD and 3026 cancer endpoints, 71% of which have bloods. With funding to extend endpoint ascertainment for 5 years, an additional 849 CVD and 1939 cancer events will accrue, with substantial increases in specific CVD events and site-specific cancers. The primary cardiovascular aim is to develop improved prediction scores for total and specific CVD outcomes that are based not only on traditional risk factors but also on novel plasma and genetic markers. The two primary cancer aims are to examine the role of randomized aspirin and vitamin E in the primary prevention of total and site-specific cancers, accounting for an adequate latent period, and to augment the usefulness of the WHS biorepository by accruing additional cancer endpoints to continue and expand our ongoing and potential collaborative and independent analyses addressing a range of genetic and environmental risk factors for cancer.